Vascular diseases (CVD) plague the US. The CDC reports the 2nd leading "actual cause" of death in the US is poor diet and physical inactivity. The theme of this PPG is that exercise (EX)-induced alterations in vascular cell phenotypes underlie the efficacy of EX in prevention and treatment of CVD. Our goals are: 1) Determine cellular/molecular mechanisms responsible for EX-induced changes in vascular cell phenotypes, 2) Apply knowledge of vascular cell biology and mechanisms of EX-induced adaptation to understanding the beneficial effects of EX on vascular disease., and 3) Determine the signals, generated by EX, that modulate vascular cell phenotype and how multiple signals interact so that healthy vascular cells are preserved in the face of poor diet. Porcine models of disease, induced with a high fat diet (HFC) will be used. Project 1 tests the hypothesis that EX confers resistance to HFC-induced, pro-atherogenic modulation of coronary smooth muscle (SM) phenotype by increasing L-type, voltage-gated Ca channel activity/expression and by preventing upregulation of store-operated Ca channels and intermediate-conductance K channels. Project 3 tests the hypothesis that EX restores/preserves normal coronary endothelial phenotype. It is proposed that altered expression of endothelial genes, such as nitric oxide synthase (eNOS), signaled by increased shear stress (Tw) during EX bouts, play key roles in EX. Project 5 tests the hypothesis that EX maintains normal endothelial phenotype through lipoprotein lipase (LPL)-dependent processes that blunt expression of proatherogenic adhesion molecules and enhance expression of anti-atherogenic genes such as eNOS. Project 6 tests the hypothesis that Tw is critical for enlargement and wall stretch (Ts) is critical for retention of very large collateral arteries sustaining perfusion following femoral artery occlusion. Tw and Ts will be increased with a unique A-V shunt placed distal to the occlusion. Interactive effects of Tw, Ts, and EX will be examined in normal and HFC pigs. The Program Project as a whole accomplishes what each individual project alone cannot;a multi-faceted approach incorporating state-of-the-art molecular, biochemical, cellular, pharmacologic, and physiologic techniques in pigs, coronary arteries, single cells and subcellular components that is unique in vascular biology and exercise science. Our unique, multi-level approach to study EX-induced vascular adaptation and the integrative collaboration stimulated by this PPG are crucial to accomplishing our stated goals. Proposed research will advance understanding of mechanisms whereby EXsustains vascular health and will lead to new/improved methods for prevention/treatment of CVD.